This proposal is concerned with the sequence of events that occur at the subcellular level in the lung during the onset of pulmonary hypertension. The clarification of these events will provide information relevant to the initiation and pathophysiology of the hypertensive response. The proposal is also concerned with the pharmacological modification of the biochemical changes occuring subcellularly with the two-fold aim of firstly; elucidating which changes are involved in initiating and which are reactive to the hypertensive process, and secondly; finding pharmacological interventions that prevent, reverse, or slow the histopathological results of pulmonary hypertension. Pulmonary hypertension will be produced in rats by administration of monocrotaline. Our preliminary work indicates that monocrotaline produces a profound inhibition of protein synthesis in the lungs (possibly indicative of decreased protein turnover) before the appearance of pathological changes. Coincident with the onset of grade 1 hypertensive changes, the calcium binding ability and ATPase activities of pulmonary microsomes are depessed. We wish to study in detail the relationship between these phenomena and the development of hypertension. The relationship between the initiation of medial hypertrophy in muscular pulmonary arteries and the hypertensive process will also be examined, using various biochemical methods to determine the point at which the hypertrophic response begins. Pharmacological interventions to be examined include the effects of lowered arterial contractility produced by inhibitors of calcium uptake into smooth muscle cells and the effects of agents that lower pulmonary blood pressure.